Natural killer (NK) cells and activated macrophages (MPhi) have been shown to inhibit formation of metastases. NK cells have effects during the bloodborne phase of metastasis, in both normal or biological response modifier (BRM)-treated mice. We have found that highly lytic NK cells can also be induced in the tissues of both the lungs and liver by the pyran co-polymer, MVE-2, and that these organ-associated NK cells are efficient in inhibiting the formation of metastases in the lungs and liver. Further, we have characterized the cells mediating this tissue resistance to metastasis as large granular lymphocytes (LGL), the cells previously associated with NK activity in rats and humans. Additionaly BRMs which augment liver-associated NK activity by inducing an influx of LGL into the liver include poly ICLC, OK-432, P. acnes, and human recombinant interleukin 2 (rIL-2). All of these BRMs induce a greater augmentation of NK activity in the liver than in blood and spleen. Further, while repeated administration of most BRMs induced a hyporesponsiveness to augmentation of NK activity in the blood and spleen, liver-associated NK activity was further augmented with additional increases in the total number of LGL. Liver-associated macrophages were also activated for tumoricidal activity by various BRMs. The application of these organ-associated natural effector cells to treatment of established liver metastases is currently under study. Similarly, we have studied the ability of rIL 2-stimulated cytotoxic lymphocytes and rIL 2 to enhance the antitumore effectiveness of the chemotherapeutic drug, doxorubicin hydrochloride (DOX). Chemoimmunotherapy of stage I murine renal carcinoma (Renca) cured 67% of Rencabearing mice, while adoptive immunotherapy or chemotherapy cured less than 20% of the mice. Further, effectiveness of chemoimmunotherapy alone was maximized against stage II or stage III Renca by a bicompartmental approach in which administration of treatment iv and ip cured greater than 75% of Renca-bearing mice, whereas iv or ip treatment produced no cures. These results demonstrate that adoptive immunotherapy can enhance the effectiveness of chemotherapeutic drugs against tumors.